key: cord-259453-1njd0c0x
authors: Nusair, Samir
title: Abnormal carbon monoxide diffusion capacity in COVID-19 patients at time of hospital discharge
date: 2020-07-23
journal: Eur Respir J
DOI: 10.1183/13993003.01832-2020
sha: 
doc_id: 259453
cord_uid: 1njd0c0x

On recovery from COVID-19 it is important to draw attention to the CO diffusion test and the actual meaning of the findings when considering the values of D(LCO) and D(LCO)/V(A) put together https://bit.ly/36k2O2Q

It is important to give emphasis here that by using carbon monoxide, D LCO represents the gas diffusion capacity across the alveolar-capillary barrier and is in fact a mathematical product of the rate constant representing alveolar carbon monoxide uptake efficiency (D LCO /V A ) multiplied by alveolar volume (V A ) [3] . Thus, when D LCO /V A is normal or near normal, D LCO may still be low because of reduced alveolar volume, which means that complete acini with alveoli and blood vessels surrounding them are affected [3, 4] . In the remaining functionally available alveolar volume, the actual carbon monoxide uptake is normal as the diffusion through the alveolar-capillary barrier is not impaired and the blood volume within the pulmonary capillary bed is not reduced. Interstitial abnormalities or pulmonary vascular abnormalities are associated with reduced D LCO /V A which accompanies reduced D LCO [4] .

In the discussion of their findings, the authors cite previous studies describing follow-up of severe acute respiratory syndrome (SARS) patients having impaired D LCO as the most common abnormality, with affected proportion of patients ranging from 15.5% to 43.6%. It would be important to describe how impaired D LCO was defined in those studies, citing values as % of predicted and comparing that with the findings of the present study.

The conclusion which can be obtained from this study is that low D LCO is caused mainly by reduced alveolar volume, and not residual interstitial abnormalities or pulmonary vascular abnormalities caused by COVID-19. The latter is important, since the proposed pathogenic mechanism describes an initial abnormality induced by COVID-19 similar to the effect of SARS and consists of a microvascular injury with some interstitial thickening with clear lungs on imaging and physical examination accompanied by profound hypoxaemia [5, 6] , followed by development of alveolar abnormalities with consequent gradual loss of the alveolar spaces [6] . The filling of the alveoli with exudate at a later stage causes the loss of lung volume and reduced pulmonary compliance [7] . The finding of decreased alveolar volume on discharge may be explained by transient changes in mechanical properties of the chest wall and respiratory muscles after critical illness and may well address the concerns about a possible long lasting pulmonary parenchymal dysfunction post-COVID-19 [2] .

In conclusion, the authors presented very useful data, but it is important to draw attention to the up-to-date manner in which we look at the carbon monoxide diffusion test and the actual meaning of the findings when considering the results of D LCO and D LCO /V A together. Impaired pulmonary function in discharged patients with COVID-19: more work ahead

We are grateful for the opportunity to respond to the letter by S. Nusair, whom we thank for his interest and thoughtful remarks about our study on the abnormal pulmonary function in coronavirus disease 2019 (COVID-19) patients [1] .

@ERSpublications Impairment of diffusion capacity is the most common abnormality in discharged patients with COVID-19. Both decreased alveolar volume and K CO contribute to the pathogenesis of impaired diffusion capacity. More follow-up work is needed. https://bit.ly/2YL2eaK Diffusing capacity of the lung for carbon monoxide (D LCO ) reflects the capacity of carbon monoxide transfer from the environment to the pulmonary capillary blood, which is the most clinically useful routine methodology to evaluate the function of the lung to exchange gas. K CO is the rate constant for carbon monoxide uptake from alveolar gas, which is influenced mostly by the thickness and area of the alveolar capillary membrane, the volume of blood in capillaries supplying ventilated alveoli, and the concentration and properties of haemoglobin in the alveolar capillary blood. D LCO is mainly determined by K CO and the alveolar volume (V A ). Mathematically, K CO can be calculated as D LCO /V A under body temperature, ambient pressure, saturated with water vapour conditions [2] .

We agree with S. Nusair that it should be noted that D LCO /V A is not a simple ratio and in fact the relationship between lung volume and carbon monoxide uptake is linear and certainly less than 1:1 [3] . Recent studies have tended to use K CO instead of D LCO /V A , as it may be inferred from the use of the term D LCO /V A that D LCO can be normalised for V A . The 2017 European Respiratory Society/American Thoracic Society standards for single-breath carbon monoxide uptake in the lung recommends that the term of K CO is preferred to D LCO /V A [2] . However, in practice, many pulmonary function test reports from different manufacturers still present with D LCO /V A and not K CO . Besides, in order for an easier and direct comparison with some previous studies on pulmonary function in patients with severe acute respiratory syndrome (SARS) [4, 5] , D LCO /V A was kept in our report. It is important to understand the interpretation of K CO and D LCO /V A , but the term of K CO is recommended for more popular use in future.

Decreased K CO occurs in alveolar-capillary damage, microvascular pathology or anaemia. Causes of low V A include reduced alveolar expansion, alveolar damage or loss, or inspired gases maldistributed with airflow obstruction. When K CO turns normal, in the presence of a low D LCO it is associated with low V A . Because only the functional alveolar units had been sampled, a biased picture toward more preserved areas of the lungs is thereby provided [3] . Crucially, the same D LCO may occur with various combinations of K CO and V A , each suggesting different pathologies. It is difficult to interpret which is the predominant role because both decreased alveolar volume and K CO contribute to the pathogenesis of impaired diffusion capacity. D LCO gives an overall assessment of gas exchange for the lung, while the alveolar-capillary membrane diffusing capacity for carbon monoxide (D MCO ) only dependents on molecular diffusion of the membranes. However, D MCO can be calculated using different equations but is not yet standardised, and as such is not a commonly used gas diffusing parameter [6] .

In our study, 51 patients with COVID-19 had impaired D LCO , including 29 patients who showed both impaired D LCO and K CO . The number of patients with both impaired D LCO and K CO (29/51) was 24% larger than the number of patients with impaired K CO alone (22/51). Moreover, the percentage of patients with decreased total lung capacity was less than the percentage of patients with decreased K CO . Furthermore, vascular injury and thrombosis have been demonstrated to be important contributing factors in the pathogenesis of COVID-19. SARS coronavirus 2 infects the endothelial cells via angiotensin-converting enzyme 2. The recruitment of immune cells to the endothelial cells facilitates the induction of endotheliitis in several organs, which contributes to systemic impaired microcirculatory function [7] . Acute pulmonary embolism has been reported during the clinical course [8] . Post mortemstudies have reported vascular injury and thrombi in multiple organs [7, 9] . ACKERMANN et al. [10] compared the lung pathology of COVID-19 with H1N1. The result showed that patient with COVID-19 presented distinctive vascular features, consisting of severe endothelial injury associated with the disruption of intercellular junctions, cell swelling and a loss of contact with the basal membrane. From the above, it is probable that the effect of membrane lesion plays an important role on the impaired diffusion capacity in patients with COVID-19.

Our study showed that, similar to D LCO , D LCO /V A (representing the transfer factor of carbon monoxide) also showed an association with the disease severity: as the patients progressed to a more severe condition, the mean value of D LCO /V A compared to predicted values was lower. Since the standard deviation values suggest that individual differences have effects on lung function, we also provided the distribution of the D LCO /V A of predicted in patients with different severities. 42% of the subjects with severe pneumonia had a D LCO /V A of less than 80% of predicted, compared to only 27% in the patients with pneumonia and 13% in patients with mild illness, respectively.

In previous follow-up studies of SARS, impaired D LCO was defined as when D LCO was <80% of the predicted value, irrespective of K CO or the alveolar volume. In follow-up studies of rehabilitating SARS patients ranging from 0.5 to 2 years, the impaired D LCO was the most common abnormality, accounting for 15.5% to 43.6% [11] [12] [13] . The mean D LCO ranged from 77.7% to 93.8% pred in the studies above, with the longest follow up of 2 years. Our study showed a mean D LCO of 78.2% pred at time of discharge but follow-up data is not available yet. It is unclear how the impaired diffusion capacity changes in survivors of COVID-19, as well as how the changes may be reflected on chest computed tomography (CT). In one study, where surviving SARS patients were seen 6 months after admission, 43(75.4%) of patients showed radiological abnormalities, including 62.8% who had abnormal D LCO [11] . Thus, the lung function impairment findings are consistent with the CT images of SARS survivors showing persistent ground glass opacity, reticular opacities and traction bronchiectasis suggesting the fibrosis [14] . Likewise, in discharged patients with COVID-19, WANG et al. [15] reported that 94% (66/70) of patients who were discharged from hospital at the end of the study still had mild to substantial residual lung abnormalities on their last CT scans.

Our study was a pilot study which first described the impaired pulmonary function in patients with COVID-19 at time of discharge. Impairment of diffusion capacity is the most common abnormality followed by restrictive ventilatory defects. However, more follow-up work is needed to assess the longitudinal variation of these deficits.

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